Submissions for variant NM_000548.5(TSC2):c.4269G>A (p.Leu1423=) (rs45438898)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000177761	SCV000169147	benign	not specified	2013-05-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000163262	SCV000213790	likely benign	Hereditary cancer-predisposing syndrome	2014-08-11	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000177761	SCV000229689	likely benign	not specified	2014-08-15	criteria provided, single submitter	clinical testing
Invitae	RCV001084395	SCV000262304	benign	Tuberous sclerosis 2	2019-12-31	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000177761	SCV000305216	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000042548	SCV000395649	benign	Tuberous sclerosis syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Integrated Genetics/Laboratory Corporation of America	RCV000590662	SCV000697469	benign	not provided	2016-08-23	criteria provided, single submitter	clinical testing	Variant summary: The c.4269G>A (p.Leu1423=) in TSC2 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.0023 (305/99578 chrs tested), including 2 homozygous occurrences. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000068). The variant of interest has been cited as Benign/Likely Benign by multiple reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000177761	SCV000711365	benign	not specified	2017-09-22	criteria provided, single submitter	clinical testing	p.Leu1423Leu in exon 34 of TSC2: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.2% (737/265766) of chromosomes, including 4 homozygotes) and the highest allele frequency of 0 .5% in Ashkenazi Jewish by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org; dbSNP rs45438898)
Athena Diagnostics Inc	RCV000590662	SCV001146285	benign	not provided	2018-09-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000177761	SCV001157411	benign	not specified	2019-01-30	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC2)	RCV000042548	SCV000066342	not provided	Tuberous sclerosis syndrome		no assertion provided	curation